D2 Biosciences
Our discovery

Two decades decoding why camptothecins stop working.

Camptothecin analogues (CPTs) are among the most widely used anti-cancer drugs, yet many patients don’t respond. Classic explanations, drug pumps and target mutations, don’t fit. Our work found the real mechanism, and turned it into a biomarker and a drug strategy.

01 · CPT-resistant pathway

Tumors destroy the drug’s own target.

We first showed in patients receiving 9-aminocamptothecin that cells degrade topoisomerase I (topoI), the target of CPTs, through the ubiquitin–proteasome pathway, and that cells which degrade topoI rapidly resist CPTs. Using functional proteomics, we identified the topoI-interacting proteins that control this degradation.

  1. STEP 1CPT binds topoI–DNADrug traps the cleavage complex
  2. STEP 2Kinase cascade firesPTEN, CTDSP1 → DNA-PKcs
  3. STEP 3 · BIOMARKERTopoI-S10 phosphorylatedMarks topoI for destruction
  4. STEP 4UbiquitinationTopoI tagged for the proteasome
  5. OUTCOMETopoI degraded → resistanceNo target, no drug effect
Diagram of topoI phosphorylation at S10, ubiquitination by BRCA1/BARD1 and degradation by the ubiquitin–proteasome pathway
Figure 1 · The CPT resistance pathway: phosphorylation at S10, ubiquitination by BRCA1/BARD1, degradation by the UPP.
02 · A predictive biomarker

Know before you treat.

Tumors with a higher basal level of phosphorylated topoI-S10 degrade topoI quickly and do not respond to topoI inhibitors. Our IHC assay, P-topoI-Dx, measures it in cells and tumor tissue. A retrospective validation in gastric and colorectal cancer patients showed very high predictive values.

  • Standard IHC workflow, existing pathology labs
  • Validated in GC and CRC cohorts
  • Positioned as a companion diagnostic
IHC staining: responders show low P-topoI-S10, non-responders show strong brown nuclear staining
Figure 2 · P-topoI-Dx staining in responders (left) and non-responders (right).
03 · Targeting CPT resistance

Three targets. Two lead compounds.

The pathway gave us three drug targets. Two complementary screening platforms produced two lead compounds that specifically inhibit CPT-induced topoI ubiquitination.

Kinase inhibitor (Ki)

An FDA-approved kinase inhibitor repurposed to block the cascade that marks topoI for degradation.

FDA-APPROVED

Novel compound

A new chemical entity with no cytotoxicity of its own: it only stops topoI from being destroyed.

NON-CYTOTOXIC
04 · Dual-payload ADC

D2-Ki: two approved payloads, one approved antibody.

Our lead compounds ride alongside a topoI inhibitor on the same antibody, so resistance is blocked in exactly the cells being treated. Approved components are designed to support rapid development with minimal risk.

D2-Ki antibody carrying two kinds of payload
  1. 1 · BINDAntibody finds the tumorApproved antibody targets a tumor antigen.
  2. 2 · ENTERADC is internalizedBoth payloads are released inside the cell.
  3. 3 · STRIKEPayload 1 traps topoITopoI inhibitor damages tumor DNA.
  4. 4 · SUSTAINPayload 2 blocks escapeKi stops topoI degradation, so the drug keeps working.
Why a dual payload? Partner with us